Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Authors:
Mingfeng Zhang Zhaoming Wang Ofure Obazee Jinping Jia Erica J Childs Jason Hoskins Gisella Figlioli Evelina Mocci Irene Collins Charles C Chung Christopher Hautman Alan A Arslan Laura Beane-Freeman Paige M Bracci Julie Buring Eric J Duell Steven Gallinger Graham G Giles Gary E Goodman Phyllis J Goodman Aruna Kamineni Laurence N Kolonel Matthew H Kulke Núria Malats Sara H Olson Howard D Sesso Kala Visvanathan Emily White Wei Zheng Christian C Abnet Demetrius Albanes Gabriella Andreotti Lauren Brais H Bas Bueno-de-Mesquita Daniela Basso Sonja I Berndt Marie-Christine Boutron-Ruault Maarten F Bijlsma Hermann Brenner Laurie Burdette Daniele Campa Neil E Caporaso Gabriele Capurso Giulia Martina Cavestro Michelle Cotterchio Eithne Costello Joanne Elena Ugo Boggi J Michael Gaziano Maria Gazouli Edward L Giovannucci Michael Goggins Myron Gross Christopher A Haiman Manal Hassan Kathy J Helzlsouer Nan Hu David J Hunter Elzbieta Iskierka-Jazdzewska Mazda Jenab Rudolf Kaaks Timothy J Key Kay-Tee Khaw Eric A Klein Manolis Kogevinas Vittorio Krogh Juozas Kupcinskas Robert C Kurtz Maria T Landi Stefano Landi Loic Le Marchand Andrea Mambrini Satu Mannisto Roger L Milne Rachel E Neale Ann L Oberg Salvatore Panico Alpa V Patel Petra H M Peeters Ulrike Peters Raffaele Pezzilli Miquel Porta Mark Purdue J Ramón Quiros Elio Riboli Nathaniel Rothman Aldo Scarpa Ghislaine Scelo Xiao-Ou Shu Debra T Silverman Pavel Soucek Oliver Strobel Malin Sund Ewa Małecka-Panas Philip R Taylor Francesca Tavano Ruth C Travis Mark Thornquist Anne Tjønneland Geoffrey S Tobias Dimitrios Trichopoulos Yogesh Vashist Pavel Vodicka Jean Wactawski-Wende Nicolas Wentzensen Herbert Yu Kai Yu Anne Zeleniuch-Jacquotte Charles Kooperberg Harvey A Risch Eric J Jacobs Donghui Li Charles Fuchs Robert Hoover Patricia Hartge Stephen J Chanock Gloria M Petersen Rachael S Stolzenberg-Solomon Brian M Wolpin Peter Kraft Alison P Klein Federico Canzian Laufey T Amundadottir

Oncotarget 2016 Oct;7(41):66328-66343

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

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http://dx.doi.org/10.18632/oncotarget.11041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5340084PMC
October 2016
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